Objectives: Studies on nontechnical risk factors for ureterovesical leak after renal transplant are scarce. This study aimed to report the possible pre- and postoperative risk factors and the role of acute rejection and antirejection therapies for urine leak after transplant and its effect on graft and patient survival.
Materials and Methods: We conducted a retrospective analysis of 13 patients (1.17%) with urine leak (case group) and 52 patients without leak (control group) (case-to-control ratio of 1:4) from 1102 living related (first degree) renal transplant recipients seen between January 2012 and December 2021. We analyzed demographic and clinical details and biochemical and outcome parameters using a nested case-control design.
Results: Cases were older than controls (P = .018), were more ABO incompatible (P = .009), and had more 6/6 HLA mismatch transplants (P = .047). Donors of cases were older than donors of controls (P = .049). The rate of postoperative hypoalbuminemia was greater in the case group (P = .050). Rates of acute rejection (P = .012) and plasmapheresis (P = .003) were greater in the case group than in the control group. On multivariate logistic regression analysis, recipient age, 6/6 HLA mismatch, and plasmapheresis were found to independently associated with urine leak. None of the patient required surgical repair, as all responded to conservative therapy. Urine leak did not affect graft outcomes (P = .324), but overall survival was less in cases than in controls.
Conclusions: Nontechnical risk factors that cause posttransplant ureteric leak include older donor and recipient age and ABO incompatible and 6/6 HLA mismatch transplants. Acute rejection and plasmapheresis predispose leak, and an indwelling double J stent can allow adequate healing of the anastomosis. High index of suspicion and prompt management are imperative to preserve graft and patient outcome.

Key words : ABO incompatible transplants, 6/6 HLA mismatch transplants, Kidney transplantation, Plasmapheresis, Urine leak

Introduction

Surgical complications of renal transplant include vascular, lymphatic, and ureteral complications. Ureteral complications like leak or obstruction can be of technical or nontechnical etiology and can contribute to substantial postoperative morbidity.1-3 Ensuring the technical safety checkpoints during ureteroneocystostomy significantly reduces incidence of ureteral complications, but existing literature is still bereft of a clear understanding of the role of nontechnical factors in causing posttransplant urine leak. Therefore, this study aimed to report the possible pre- and postoperative risk factors and the role of acute rejection and antirejection therapy in posttransplant urine leak and its impact on graft and patient survival.

Materials and Methods

After institutional ethics committee approval, we conducted a retrospective analysis of 1102 patients who underwent living related (first degree) renal transplant between January 2012 and December 2021 at a high-volume transplant center in India. Demographic profiles, clinical details, and bioche-mical and outcome parameters of recipients and donors were analyzed. A serial number was assigned to each case and was entered in the transplant database.

Immunosuppression protocol
The induction immunosuppression among patients included antithymocyte globulin in patients with high immunological risk and basiliximab (anti CD25) or no induction in patients with low immunological risk. ABO-incompatible donors underwent a desen-sitization protocol that included rituximab (anti-CD20) on day −10 followed by plasmapheresis with intravenous immunoglobulin administration to achieve anti-ABO titer (1:8). The maintenance immunosuppression was a 3-drug regimen that included a calcineurin inhibitor (tacrolimus), an antimetabolite (mycophenolate mofetil), and corticosteroids.

Surgical protocol
All renal transplants were performed by experienced surgeons with transplant experience ranging from 8 to 26 years. All left-sided donor nephrectomies were done laparoscopically. The right-sided nephrectomies were lap-assisted open nephrectomies, with special care to preserve the golden triangle.
End-to-side anastomosis with external iliac artery was performed in cases with a single renal artery. Multiple donor renal arteries were anastomosed either separately or by pantaloon anastomosis to the external iliac artery or by end-to-end anastomosis of smaller artery to the inferior epigastric artery. Prophylactic use of anticoagulants in multiple-vessel anastomosis is not part of our institutional protocol. The extravesical stent, tunneled Lich- Gregoire technique was used for ureterovesical anastomosis. Extreme care was taken to avoid inadvertent injury to the surrounding bladder with monopolar cautery during vesicostomy. A retroperitoneal closed suction drain was placed in every case. The double J stent was removed at 2 weeks postoperatively. The surgical drain was removed on the third or fourth postoperative day when the drain output was less than 50 mL/day.

Rejection
Patients with antibody-mediated rejection were treated with plasmapheresis and intravenous immunoglobulin (0.4 g/kg/session) infusion. Patients with T-cell-mediated rejection were treated with pulse steroid therapy of methylprednisolone (500-1000 mg/day) for 3 days. Antithymocyte globulin (1.5 mg/kg/day) was used to treat patients who did not respond to steroids. Patients with mixed rejection received methylprednisolone along with plasmapheresis.

Ureterovesical leak
Patients with suspected ureterovesical leak had a wide spectrum of clinical presentation. The leak was confirmed by imaging (ultrasonography, computed tomography cystogram, or antegrade pyelography) and drain fluid creatinine level.
We identified 13 patients (1.17%) with urete-rovesical leak during the study period (case group). We identified 52 patients without leak (control group). Ratio of case to control was 1:4, with results analyzed in a nested case-control design; 4 controls for each case is suggested as the ideal sample size in a nested case-control design.^4,5 According to their number in the transplant database, we identified 2 patients above and below an identified case as the control. For example, if the identified case has a transplant number “x” in the transplant database, then x - 1, x - 2, x + 1, and x + 2 were taken as their respective controls. Only living donor transplants were included in the study to improve matching.

Statistical analyses
We used the Statistical Package for Social Sciences, version 23 (IBM), for statistical analysis. Normality distribution of the continuous variables was tested, and a variable was considered normally distributed when the Z value of the skewness was found within ±3.29. Independent sample t test was used to compare the means between 2 groups, whereas the Fisher exact test was performed to test the association (or compare the proportions) between 2 categorical variables. We used Kaplan-Meier analysis (using log-rank test) with corresponding survival plot to compare the survival time between cases and controls. Binary logistic regression analysis was used to identify the significant predictors of the ureterovesical leak. P ≤ 0.05 was considered significant.

Results

Mean age of the 65 study patients was 38.52 ± 10.99 years (range, 12- 67 y), and most patients were males (n = 55, 84.61%). Cases were significantly older than the controls (45.17 ± 12.49 vs 36.85 ± 10.05 y; P = .018) (Table 1). The mean native kidney urine output in the study group was 307 ± 179.96 mL (range, 0-2000 mL), and the mean duration on dialysis was 16.18 ± 11.12 months (range, 1-65 mo) before transplant. A normal capacity and compliant bladder with no bladder outlet obstruction was ensured in all patients. Variables such as sex, native kidney disease, pretransplant diabetic status, history of previous transplant, choice of induction immunosuppression, pretransplant urine output, and dialysis vintage were comparable between the groups. The case group had significantly more ABO-incompatible (38.5% vs 9.6%; P = .009) patients and transplants with 6/6 HLA mismatch (2 each from HLA-A, HLA-B, and HLA-DRB1) (30.7% vs 11.5%; P = .047) compared with the control group.

Donors of cases were older than donors of controls (45.80 ± 10.05 vs 40.6 ± 7.49 y; P = .049). Most donors were female in both the case and control group. As a part of our institutional protocol, people with diabetes are not considered for donation; however, hypertension (cases: 23%, controls: 15.4%) and hypothyroidism (cases: 15.4%, controls: 13.4%) were common comorbidities in both groups. Donor sex, body mass index, comorbidities, multiple renal arteries, and surgical approach (laparoscopic vs lap-assisted open) were not significantly different between the 2 groups (Table 1).

Mean serum albumin level posttransplant (measured over 2 weeks) was significantly lower in recipients in the case group (2.72 ± 1.08 vs 3.47 ± 1.18 g/dL; P = .050), but there were no significant differences in posttransplant anemia, hyperglycemia, and urinary tract infection between the 2 groups (Table 1).

Rejection and antirejection therapy
In the study group, 18 patients underwent kidney biopsies (6 from the case [leak] group and 12 from the control group) after transplant because of a clinical suspicion of rejection. Five patients (38.4%) from the leak group showed acute rejection, and 4 (7.7%) from the control group had rejection (P = .012). Eight of the 12 biopsies from the control group were either negative (no evidence of rejection) or showed acute tubular necrosis. The most common type of rejection was antibody-mediated rejection, which accounted for 4 cases in the leak group and 3 cases in the control group. These patients received antirejection therapy according to the type and severity of rejection and the immunological status. Six patients (46.1% from the case [leak] group, including 5 patients with biopsy-proven rejection and on an empirical basis for 1 patient) and 5 patients (9.6%) from the control group received plasmapheresis (P = .003) (Table 1).

On multivariate logistic regression analysis (adjusted for recipient age, ABO incompatibility, 6/6 HLA mismatch, donor age, postoperative mean serum albumin, acute rejection, plasmapheresis) (Table 2), we found that recipient age, 6/6 HLA mismatch, and plasmapheresis were independently associated with urine leak.

Management and follow-up
None of the study patients required surgical repair as all responded to conservative therapy (Table 3). Patients who presented early (<day 14 posttransplant) with double J stent in situ were managed with a prolonged indwelling per-urethral catheter (14 days) and double J stent (3 months). In patients who presented with leak after stent removal (day 14 posttransplant or later), urinary diversion by percutaneous nephrostomy and antegrade double J stenting (for 3 months) were shown to be beneficial (Figure 1).

The mean follow-up duration was 34.23 ± 20.3 months (range, 12-82 mo). No additional procedure was required in any patient. The mean serum creatinine level in the leak group at the last follow-up was 1.12 ± 0.33 mg/dL (range, 0.62-2.77 mg/dL), which was comparable with the control group.

There were 6 deaths during follow-up, and 3 patients were lost to follow-up. Of 3 patients lost to follow-up, 2 were from the control group and 1 was from the case (leak) group. Three patients from the case group and 3 from the control group died from infective/septic complications.

The Kaplan-Meier survival analysis was done to compare the overall survival between the 2 groups. Results showed an equal number (3 [25%] and 3 [6.3%]) of events (death) in the case and control groups. The mean and median survival times in the case group were 37.83 months (95% CI, 29.22-46.45) and 43.00 months (95% CI, 0.0-96.53); in the control group, mean survival time was 76.53 months (95% CI, 70.67-82.40), and median time could not be recorded as the survival probability never reached below 50% (Figure 2).

Discussion

After renal transplant, ureteral complications have been reported in 2.9% to 21% of patients,^6-9 with ureterovesical leakage occurring in 0% to 9.3% of cases.^1,10-12 In our series of 1102 patients over a period of 9 years, the incidence of leak was 1.17%, with time of presentation ranging frkom day 5 to day 32 after transplant. Leaks from surgical errors usually present early (in the first 24 hours), whereas those from ureteric ischemia or necrosis occur within the first 14 days.^3,13,14

Evidence has suggested that laparoscopic donor nephrectomy does not increase the incidence of ureteral complications.^3,15-17 Preserving the golden triangle during donor nephrectomy and keeping the ureter short and tension-free before ureterovesical-stented anastomosis, with pink bleeding lower margins, ensured proper vascularity in our study patients. Extravesical stented anastomosis has a comparatively lower incidence of ureteral complications^18-20 and is therefore our preferred choice.

Among the nontechnical factors, older age of the recipient, ABO incompatibility, and 6/6 HLA mismatch significantly contributed to presence of leak in our study patients. Although older age has been reported as a risk factor,² ureteral leaks are also common in pediatric recipients^21,22 because of either higher graft position necessitating either longer ureter or uretero-ureteric/pelvic-ureteric anastomosis or an abnormal bladder.²³ The leak has been reported to be common in males,^1,3 but no such observation was seen in our study. ABO incompatibility and 6/6 HLA mismatch commonly require heightened immuno-suppression postoperatively, which delays wound healing. Although antithymocyte globulin for induction immunosuppression was preferred for high-risk transplants, the choice of induction agent did not correlate with leak. Pretransplant urine output and dialysis vintage can affect bladder cycling, but neither of these factors was associated with increased leak in our study cohort. The lack of published literature correlating these factors precludes any definitive conclusion.

Apart from older donors, no other donor-related factors significantly contributed to the leak in this cohort. Vascular inconsistency in older donors has been attributed to ureteric ischemia.^2,12,24 Every effort should be made to preserve the lower pole accessory artery to preserve the vascularity of the distal ureter,²⁵ ligation or thrombosis of which might lead to distal ureteric necrosis,¹⁴ thereby making multiple arteries a risk factor for ureteric complications.^1,11 As per protocol, all accessory renal arteries, especially the lower pole, were anastomosed either end to side to external iliac artery or end to inferior epigastric artery, depending on the arterial caliber and the percent parenchymal area supplied by it. Therefore, the presence of multiple renal arteries did not significantly contribute to leak in our cohort.

Stented anastomosis is accepted to reduce early postoperative ureteral complications.^2,26,27 Continuous drainage, splintage for a linear ureteric alignment without kinking, protection from luminal narrowing due to postoperative edema or external compression, and allowing healing of small localized necrotic areas are the presumed advantages.^25,28,29 Therefore, an indwelling double J stent for 14 days is a normal protocol for all of our patients. A decision to prolong the duration of indwelling stent to 4 to 6 weeks was based on intraoperative observation of a thin ureter or an adhered or frail bladder mucosa.

Unlike postoperative anemia, incidence of leak was greater in patients with postoperative hypoal-buminemia, which can be attributed to poor nutritional status and, therefore, poor wound healing. Pretransplant diabetes or posttransplant hyper-glycemia was not significantly associated with leak in our cohort and is considered as an inconsistent contributory factor.²⁵ Patients who developed rejection and received immunosuppression had more incidence of leak. Acute rejection and delayed graft function are known to cause ureteric ischemia.^{12,18,25,30-32} High-dose steroids^12,23,25,33 and plasmapheresis delay wound healing, increasing the chances of a leak, as also seen in our study. This can also be attributed to ureteral edema, leading to impaired arterial flow and venous drainage.^12,34 A prolonged indwelling stent (6 weeks) in such patients could be beneficial until the edema subsides.

Unresolved high drain output, a sudden increase in drain output with fall in urine output, pain and perigraft collection after per-urethral catheter removal, and a sudden drop in output after double J stent removal are common clinical presentations. Computed tomography cystogram, isotope renogram, single-photon emission computed tomography, or computed tomography fusion can be used to visualize and localize leakage.^13,35,36 A high index of clinical suspicion supported by high creatinine levels with drain fluid or leak demonstrated on antegrade nephrostogram is diagnostic^14,25,37 and forms the diagnostic protocol at our center.

All patients responded to conservative manage-ment, with none requiring surgical reexploration. Continuous bladder drainage with prolonged catheterization (14 days) with long indwelling stent (3 months) facilitated healing of the anastomosis. Maximal decompression (percutaneous nephrostomy) and urinary diversion (double J stenting) can successfully manage leaks due to small necrotic areas or due to delayed wound healing.^{3,14,22,23,38,39} Percutaneous drainage of large collection reduces risk of infection^8,40 as done in 6 of 13 patients in our study.

Unlike ureteric obstruction, a ureteric leak is not associated with graft loss,^3,25,41 as also observed in our study. High incidence of infective/sepsis-related mortality in our cohort can be attributed to irregular follow-up, poor socioeconomic status, literacy level, and consequently poor patient compliance, especially during the COVID-19 pandemic. The decreased survival, evident in the case (leak) group in our study, may be from the increased number and severity of acute rejections in the group and the related complications and may not be directly related to the ureteric complications.

As a limitation, the retrospective nature of this single-center cohort analysis precludes direct causality between risk factors and ureterovesical leak.

Conclusions

Our study highlights the importance of nontechnical risk factors for causing posttransplant ureteric leak, such as older donors and recipients, ABO incompatible, and 6/6 HLA mismatch transplants. Acute rejection and plasmapheresis predispose leak, and an indwelling double J stent can allow adequate healing of the anastomosis. High index of suspicion and prompt management are imperative to preserve graft and patient outcome.

References: